1. Field of the Invention
The present application pertains to N-mustard compounds, methods for their preparation, pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions in therapy and treatment, for example, of cancer.
2. Description of the Related Art
Gene-targeting agents, such as N-mustards, have played an important part in anticancer drug development.1 Drawbacks of using DNA-alkylating agents include their high reactivity resulting in loss of therapeutic activity against malignancy by reacting with other cellular components such as proteins, thiols or genes,2 lacking of intrinsic DNA binding affinity of the core N,N-bis(2-chloroethyl)amine pharmacophore and a requirement for bifunctional crosslinking of DNA to be fully cytotoxic resulting in lower their potency and producing high ratio of genotoxic monoadducts to crosslinkers (up 20:1).3 It has demonstrated that the targeting mustards to DNA by attaching to DNA-affinic carriers facilitates in finding compounds of higher cytotoxicity and potency than the corresponding untargeted N-mustard moiety. There is renewed interest in these general class of drugs, following recent demonstrations that both their sequence and regioselectivity of DNA alkylation can be altered by attaching them to a variety of DNA-affinic carriers (such as DNA-intercalators or DNA minor groove binders) and that can result in a modified spectrum of biological activity.4-14 
Among DNA-targeting mustards using 9-anilinoacridines as a DNA-affinic carrier, compound 1 and 2, were less cytotoxic than amsacrine (3) and the 4-linked analogues (1) showed slightly higher in vivo antileukemic activity than their corresponding 1′-linked analogues (2), indicating that the N-mustard residue would prefer to be linked to the acridone chromophore to have better cytotoxicity.10 In contrast, our recent research on development of gene-targeting N-mustards demonstrated that alkyl N-mustard linked to the anilino ring or acridine chromophore of 9-anilinoacridines, such as (3-(acridin-9-ylamino)-5-{2-[bis-(2-chloroethyl)amino]-ethoxy}phenylmethanol (4, BO-0742)15,16 and N1-(4-{2-[bis(2-chloroethyl)-amino]-ethoxy}acridin-9-yl)-5-methoxybenzene-1,3-diamine hydrochloride (5, BO-0940),17 respectively, were significantly more cytotoxic (>100-time) than 3-(9-acridinyl-amino)-5-hydroxymethylaniline (AHMA, 6)18,19 in inhibiting various human leukemia and solid tumor in vitro and in vivo. Formulae of the compounds discussed in this paragraph is shown in FIG. 1.
N-mustard derivatives, in general, have a short half-life in mice and human plasma. Our unpublished results showed that the half-life of BO-0742 in mice is about 25 min. To overcome the chemical instability of N-mustards, a number of aziridinylnitrobenzamides20,21 (i.e., 7, CB 1954, Scheme 1) and 5-[N,N-bis(2-haloethyl)amino]-2,4-dinitrobenzamides (9)20 or aniline and benzoic acid mustards linked to L-glutamic acid moiety through a urea or carbamic acid ester linkage (11, Scheme 2)22 or carboxamide (13, CMDA)22 have been synthesized as candidate prodrugs for gene-directed enzyme prodrug therapy (GDEPT).23 The electro-withdrawing aromatic nitro function of the aziridinyinitrobenzamides can be reduced efficiently to the active electron-donating hydroxyamino by E. coli nitro-reductase (NR) (Scheme 1). The activation of the glutamic acid containing mustards requires carboxypeptidase G2 (CPG2). It has demonstrated that these prodrugs were effective substrates for the enzyme and showed to have improved therapeutic activity in CPG2-expressing xenografts.24-32


Therefore, there is a need for a new potent DNA-targeting alkylating agents having a long half-life in human plasma.